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Early Use of Insulin to Improve Beta Cell Preservation

By David Joffe, BSPharm, CDE; Steve Freed, BSPharm CPT; Brandon Flohr, PharmD, and Vanessa Cepero, PharmD, CVS Pharmacy

Type 2 diabetes is a heterogeneous disorder, characterized by glucotoxicity, beta cell dysfunction and decreased insulin sensitivity. Presence of amyloid deposits in the islets and decreased beta cell mass are the pathological hallmark of the disease1.

Several clinical and experimental studies have clearly shown that even minimally preserved beta cell function is metabolically beneficial. This leads to lower HbA1C levels, lower insulin dosage and lesser metabolic decompensation after insulin withdrawal.


Using hyperglycemic clamp studies for quantitative assessment of beta cell function has clearly shown that it is the most important determinant of glucose disposal. It has also been found to be a major contributor to oral glucose tolerance even in high risk relatives of type 2 diabetic patients in different ethnic groups. Beta cell function is quantified as the ratio of the incremental insulin to glucose responses over the first 30 minutes during the Oral Glucose Tolerance Test (OGTT) was found to be more important in determining glucose disposal. This result was valid even after adjustment for insulin sensitivity, which might modulate beta cell function.2

Beta cell dysfunction is responsible for various defects observed in type 2 diabetics, individuals with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and include those genetically predisposed to develop type 2 diabetes.3 These defects include:

a. Diminished first and second phase insulin release

b. Decreased pulsatile or oscillatory insulin release

c. Increased release of proinsulin-like molecules and

d. Impaired ability to compensate for superimposed tissue insulin resistance.



This is almost a requisite slide when beta-cell dysfunction is discussed. It really does show, in a nice linear pattern, the pathogenesis of type 2 diabetes over time. When patients do not exercise, they become more obese, and as part of the normal aging process, insulin resistance increases. In response to increasing insulin resistance, beta cell secretes more insulin and amylin; all this is the normal physiological state. What happens is that in those susceptible individuals beta-cell function begins to decline. This decline of beta-cell function — in the face of usually severe but stable insulin resistance — leads to first postprandial hyperglycemia (in most cases) and then fasting hyperglycemia. Our job is to try to figure out why this decline in beta-cell function is happening, what can we do about it when it occurs, or how can we prevent it.


The United Kingdom Prospective Diabetes Study (UKPDS) has clearly shown that irrespective of the treatment modalities used, there was a progressive decline in beta cell function over time.4  Notwithstanding the genetic predisposition (apoptosis), there are several acquired and reversible factors which can accelerate the beta cell dysfunction. They include:

Image_3a. Obesity
b. Insulin resistance
c. Glucotoxicity
d. Lipotoxicity
e. Inflammation
f. Alterations in incretins – Glucagon-like peptide-1 (GLP-1), gastric inhibitory peptide (GIP)
g. Malnutrition in uterus and in early life, which may affect programming of the beta cells with respect to glucose sensing, apoptosis, regeneration and a bility to compensate for IR.
h. Functional defect of beta cell, as evidenced by greater than 80% reduction in insulin release with only 20 – 40 % reduction in beta cell mass.


While several strategies can be employed to tackle many of these factors contributing to beta cell decline, insulin alone has the most salutary effect on majority of them. Both acute and prolonged hyperglycemia adversely affects beta cell function.5 Glucotoxicity leads to impaired gene transcription, down-regulation of glucose transporters and alteration of transporter function induced by oxidative stress.6 Early use of insulin results in increased insulin gene expression and insulin synthesis. It provides rest to beta cells, already stretched to their capacity and helps them regenerate over time. Beta cells are most stressed and therefore most vulnerable to programmed cell death (apoptosis) during the first few months following the clinical onset of diabetes. Quick restoration of euglycemia by early insulin therapy at this stage will naturally preserve beta cell function on a long term basis. This has been demonstrated in several experimental and clinical studies.

In Chinese hamster, a spontaneous and selectively inbred animal model for non-obese type 2 diabetics, two weeks of normalization of glycemia resulted in marked improvement in beta cell function. This was characterized by improved beta cell signaling induced by the cyclic AMP protein kinase A pathway. This was also associated with improved islet insulin content and beta cell morphology as demonstrated by immunocytochemistry.7 In patients with Latent Autoimmune

Diabetes of Adults (LADA), early initiation of insulin has been shown to preserve beta cell function. This was evidenced by preserved C-peptide response compared to baseline in insulin treated group, as compared to Sulfonylurea (SU) group, which showed significantly lesser

C-peptide after two years. This worsened further at the end of three years8. It has also been demonstrated that short term glycemic control by intravenous insulin infusion restores SU sensitivity in significant proportion of non-obese SU nonresponsive type 2 diabetic subjects. These patients showed a significant improvement of metabolic control and beta cell secretion. During the 6-month follow up period they could be managed with glibenclamide alone. Metabolic improvement was associated with improvement in fasting and post meal C-peptide levels as well.9

A number of in vitro and animal studies have demonstrated that chronic elevation of free fatty acid impairs beta cell function (Lipotoxicity). Free fatty acid (FFA) also antagonizes the action of insulin, both on glucose production and glucose utilization.10 It also promotes Gluconeogenesis and enhanced Glucose 6-phosphatase gene expression, which directly increases glucose production. Increased beta cell concentration of fatty acid co-A, TNF-alpha, resistin, leptin, adipsin and amylin and tissue accumulation of lipids all contribute to the inexorable decline in beta cell function.11 Early insulin therapy is known to mitigate the deleterious effects of these molecules directly or indirectly.  

Glucose effectiveness: In normal individuals glucose is master regulator of the glucose flux in the tissues. In type 2 diabetics, presence of hyperglycemia fails to suppress glucose production and also fails to stimulate glucose utilization. It has been shown that only 3 days of intensive insulin therapy regains normal effectiveness of glucose to suppress glucose production and stimulate glucose utilization in response to hyperglycemia.12 During this study it was concluded that the mechanism through which glucose effectiveness was restored included improved glycogen synthesis and decreased level of circulating FFA.

Inflammation has been identified as an important determinant in the pathogenesis of beta cell dysfunction. Several pro-inflammatory transcription factors have been identified which inflict damage to the beta cells through liberation of large numbers of inflammatory cytokines.13

It has now been established that our daily macronutrient intake is largely proinflammatory. It leads to oxidative stress, generation of reactive oxygen species and expression of proinflammatory transcription factor NFkB. Resultant liberation of cytokines like, intercellular adhesion molecules-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), p-selectin and others initiate and perpetuate the inflammation induced damage to the beta cells. In the context of macronutrient intake, prompt and adequate insulin response counteracts the expression of NFkB and subsequent inflammatory cascade. This inhibits any inflammation induced damage to the beta cells. Insulin in this respect can be viewed as the natural anti inflammatory molecule. Elegant studies have shown remarkable reduction in the level of NFkB, ICAM-1, p-47, Reactive Oxygen Species (ROS) etc by insulin administration.14

Loss of first phase insulin response (FPIR) has emerged as one of the most important factor in the pathogenesis of type 2 diabetes and occurs prior to the diagnosis of diabetes. Its magnitude correlates with the degree of beta cell dysfunction.15  Its consequences include:
a. Inadequate inhibition of endogenous glucose production.
b. Rise in non esterified fatty acids (NEFA) due to inadequate antilipolytic action of insulin.
c. Inadequate priming of insulin sensitive tissues leading to decreased glucose disposal.
d. Altered signaling capacity of hormones leading to insulin resistance.
e. Enhanced stimulatory action of glucagon on gluconeogenesis.
f. Enhanced post prandial hyperglycemia
g. Increased risk of micro and macrovascular complications.

It is also important to understand the correlation between levels of glycemia and loss of FPIR:

  • FPIR is mostly absent when the FPG is more than 109 mg/dl
  • When FPG is > 140 mg/dl 75% of beta cell function is lost.16
  • When FPG is > 180 mg/dl there is complete loss of FPIR.
  • When 2 hrs PG values are > 200 mg/dl there is marked reduction in FPIR.17
  • Even in subjects with IGT there is marked reduction in the FPIR.

Considering these facts it seems prudent that all attempts be made to restore FPIR. This would logically correct or mitigate all the consequences mentioned above. Additional benefits would include beta cell rest, reduced hyperinsulinemia of the late phase after ingestion of a meal, reduced production of islet amyloid peptide and improved insulin secretion over time. Excessive accumulation of amyloid deposits between islet cells and capillaries leads to destruction of islet endocrine cells and progressive worsening of beta cell function. Current paradigm of using sulfonylureas (SU) in majority of type 2 diabetic patients leads to increased deposition of amyloid deposits and faster decline in beta cell function.18 However insulin sparing sulfonylureas (Glimepiride) and non-sulfonylureas secretagogues (Repaglinide and Nateglinide) may not produce this undesired effect.

Bruttomesso et al have shown that intra venous infusion of insulin during the first 30 minutes of an OGTT markedly improved glucose tolerance by restoring FPIR. It was clearly demonstrated in this study that neither a continuous infusion of insulin nor delaying the infusion beyond 30 minutes achieved similar benefit.19 This implies the importance of the timing of insulin administration. Several other studies have used subcutaneous Lispro, Aspart and others to demonstrate similar benefits; thus assuring translation of these benefits of restoring FPIR in clinical practice. These studies have shown that the restoration of FPIR by intensive insulin treatment leads to improved insulin secretion and long term glycemic control.20 This may pave way to withdraw insulin for several years.

Case Study: A 42 year old Mexican American presented with a average blood glucose of 383 mg/dl. The patient was started on insulin therapy with NPH and Regular and was able to lower fasting blood sugar down to an average of 110mg/dl in two weeks. After four weeks the patient was developing severe hypoglycemia. The insulin was decreased and then soon after discontinued. From the results it was concluded that early insulin treatment can improve beta cell function.21


Insulin possesses the unique ability to correct majority of the reversible factors contributing to the inexorable decline of beta cell function in the natural history of type 2 diabetes. Early initiation of insulin addresses the issues of glucotoxicity, lipotoxicity, inflammation, first phase insulin response, insulin resistance and many other factors. Backed by solid pathophysiological rationale and evidenced by animal and human studies, it sounds prudent to shift the paradigm of insulin administration in type 2 diabetes from one of ‘last resort’ to ‘first assault’.

Practice Pearls: 

  • By removing the glucolipotoxicity you can improve beta cell function.
  • Since Type 2 diabetes is a progressive disease and will worsen over time. By improving beta cell function the progression of diabetes can be slowed down to prevent complications.
  1. Hoppener JWM, Ahren B, Lips CJM. Islet amyloid and type 2 diabetes mellitus. N Engl J Med 2000;343:411-419.
  2. Jensen CC, Cnop M, Hull RL, et al for the American Diabetic Association GENNID study group. Diabetes 2002;51:2170-2178.
  3. Jerich JE, Smith TS. ß-cell defects and pancreatic abnormalities in type 2 diabetes. In: Pickup JC, Williams G Eds Textbook of Diabetes, Third edition. Massachusetts, USA Blackwell Publishing company 2003;23.1-23.11.
  4. United Kingdom Prospective Diabetes Study Group (UKPDS). Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 1998;352:837-853.
  5. Meyer J, Sturis J, Katschinski M, et al. Acute hyperglycemia alters the ability of the normal beta-cell to sense and respond to glucose. Am J Physiol Endocrinol Metab 2002;282:E 917-922.
  6. Yki-Jarvinen H. Glucose toxicity. Endocr Rev 1992;13:415-431.
  7. Kohnert KD, Hehmke B, Kloting I, et al. Insulin treatment improves islet function in type 2 diabetic Chinese hamsters. Exp Clin Endocrinol Diabetes 2001;109:196-202.
  8. Kobaysh T, Nakanishi K, Murase T, et al. Small doses of subcutaneous Insulin as a strategy for preventing slowly progressive ß-cell failure in islet-cell antibody positive patients with clinical features of NIDDM. Diabetes 1996;45:622-626.
  9. Sinagra D, Greco D, Amato MC, et al. A 12-h intravenous insulin infusion restores the ß-cell response to sulfonylureas in patients affected by type 2 diabetes. Diabetes Care 2000;23:1857-1858.
  10. Poitout V, Roberson R. Minireview: secondary beta-cell failure in type 2 diabetes- a convergence of glucotoxicity and lipotoxicity. Endocrinology 2002;143:339-342
  11. Ahima R, Flier J. Adipose tissue as an endocrine organ. Trends Endocrinol Metab 2000;11:327-332.
  12. Hawkins M, Gabriely I, Wozniak R, et al. Glycemic control determines hepatic and peripheral glucose effectiveness in type 2 diabetic subjects. Diabetes 2002;51:2179-2189.
  13. Dandona P, Alijada A, Mohanty P. The anti-infl ammatory and potential anti-atherogenic effect of insulin: a new paradigm. Diabetologia 2002:45:924-930.
  14. Alijada A, Ghanim H, Dandona P, et al. Insulin inhibits NFkB and MCP-1 expression in human aortic endothelial cells. The J of Clin Endocrinol and Metab 2001;86(1):450-453.
  15. Seshiah V, Balaji V. Early Insulin Therapy in Type2 Diabetes. Int. J. Diab. Dev. Countries 2003;23:90-93.
  16. Porte D Jr. Banting Lecture 1990. Beta-cells in type II diabetes mellitus. Diabetes 1991;40:165-180.
  17. DeFronzo F. The triumvirate: ß-cell, muscle and liver: a collusion responsible for NIDDM. Diabetes 1988;347:667-687.
  18. Rachman J, Levy JC, Barrow BA, et al. Changes in Amylin and Amylin like peptide concentration and b-cell function in response to sulfonylurea or insulin therapy in NIDDM. Diabetes Care 1998;21:810-816.
  19. Bruttomesso D, Pianta A, Mari A, et al. Restoration of early rise in plasma insulin levels improves the glucose tolerance in type 2 diabetic patients. Diabetes 1999;48:99-105.
  20. Ilkova H, Benjamin G, Aydin T, et al. Induction of long term glycemic control in newly diagnosed type 2 diabetic patients by transient intensive insulin treatment. Diabetes Care 1997; 20: 1353-1356.
  21. Mayfield JA, White RD. Insulin Therapy for Type 2 Diabetes: Rescue, Augmentation and Replacement of Beta-Cell Function. Am Fam Physician. 2004;70(3):489-500.
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